The present invention relates to the field of bone morphogenetic proteins and more particularly to a gene in the BMP-1/Tld family of genes.
Bone formation in mammals such as mice and humans is governed by a set of bone morphogenetic proteins (BMP). Of the seven BMPs known to participate in osteogenesis, six (designated BMP-2 through BMP-7) belong to the TGF-.beta. super family. The seventh BMP (designated BMP-1) is not TGF-.beta.-like, but instead appears to derive from a different gene family. The BMP-1 gene family members typically contain the following domains: an astacin-like metalloprotease domain, one or more EGF-like motifs which in other proteins are thought to bind Ca.sup.++, and a number of CUB domains. A CUB domain is a motif that mediates protein-protein interactions in complement components C1r/C1s which has also been identified in various proteins involved in developmental processes. BMP-1 was described, at the nucleotide sequence level, by Wozney, J. M., et al., Science 242:1528-1534 (1988).
The mammalian BMP-1 domain structure is shared by proteins found in other non-mammalian species. These proteins include Drosophila tolloid (Tld) (Shimell, M. J., Cell 67:469-481 (1991)), a tolloid-like Drosophila gene product (Tlr-1 or tolkin) (Nguyen, T., Dev. Biol. 166:569-586 (1994) and Finelli, A. L., et al., Genetics 141:271-281 (1995)), a sea urchin BMP-1 homolog (suBMP-1) (Hwang, S.-P., et al., Development 120:559-568 (1994)), two related sea urchin developmental gene products, SpAN and BP10 (Reynolds, S. D., et al., Development 114:769-786 (1992) and Lepage, T., et al., Development 114:147-164 (1992)), a Xenopus BMP-1 (xBMP-1) (Maeno, M. et al., Gene 134:257-261 (1993) and a mammalian tolloid (mTld) (Takahara, K. et al., J. Biol. Chem. 269:32572-32578 (1994)). A tolloid-like gene (xolloid) obtained from Xenopus has been briefly mentioned in passing in a article reviewing the astacin family of metalloproteases. Bond, J. S. and R. J. Benynon, Protein Science 4:1247-1261 at 1249 (1995), but data relating to the gene itself has not been published. Some of the nucleic acid sequences of the genes that encode these proteins are known. The mammalian BMP1 gene encodes both the BMP-1 protein and the mTld protein, albeit on two distinct, alternately spliced mRNA molecules. The papers mentioned in this paragraph are incorporated herein by reference.